The clinical literature is replete with studies that characterize structure and diversity of the gut microbiome through sequencing the 16S RNA gene and correlating the results to different disease states, including obesity. Yet, fundamental questions remain: Does the make-up of the gut microbiome matter in the development of obesity from the perspective of quantitative bioenergetics? How might we monitor and manipulate the gut microbiome to optimize its positive impact on the host? Two key findings from the existing literature support the critical role of the gut microbiome on body weight and point us towards answers to these two key questions. First, animal models support the global hypothesis that the composition of the gut microbiome leads to obesity via multiple mechanisms, including more energy extraction from foods. Second, the literature suggests that host factors -- namely, genetics and metabolic status -- play important roles in host/gut microbiome interactions. We hypothesize that the gut microbiome contributes to the host's energy balance in a quantifiable way and that we can change the magnitude of that contribution by managing microbial interactions and activity through diet. Aim 1: Create, test, and refine an integrated in silico model of energy balance in a metabolic ward setting using a typical Western diet vs. a Microbiome Enhancer (ME) diet consisting of whole foods. Clinical and laboratory data will be inputs to develop, test, and refine the model of microbial ecology/metabolism. Once the model is well developed, we will compare model outputs (predictions) to directly measured (observed) energy absorption using state-of-the-art metabolic-ward techniques. Aim 2: Explore the effect of a Western vs. ME diet on proximal and distal gut enteroendocrine secretions, gastric emptying, and small bowel transit time and relate these results to subjective hunger/satiety and measured food intake. Aim 3: Using modeled and measured energy balances, quantify the effect of a Western diet vs. ME diet on the microbial contribution to energy balance. Significance and Innovation: We have created a novel model that explicitly links the effects of microorganisms on human energy balance and modeled weight change. In addition, our proposed metabolic ward studies will make it possible for us to measure small changes in energy absorption, TDEE, and/or food intake that affect long-term weight gain or loss. The effects of changes in the microbial ecology on energy expenditure (EE) or food intake have never been studied under controlled metabolic ward conditions. Impact: These studies will, for the first time, quantify the gut microbiota contributions to the host's energy balance. By integrating clinical measurements, bioreactor experiments, and mathematical modeling, we will be able to describe cause-and-effect mechanisms. The studies will allow us to distinguish among effects stemming from a net change in energy absorption vs. alterations in energy expenditure and effects on hunger/ satiety. Our innovative methods also will provide quantitative insights to the microbiota contribution and enable future studies on the interacting roles of diet, the gut microbiome, and human physiology.